Yamamoto N, Zou J P, Li X F, Takenaka H, Noda S, Fujii T, Ono S, Kobayashi Y, Mukaida N, Matsushima K
Biomedical Research Center, Osaka University Medical School, Japan.
J Immunol. 1995 Mar 1;154(5):2281-90.
Spleen cells from BALB/c mice bearing a syngeneic tumor (CSA1 M) 2 to 3 wk after inoculation with CSA1 M cells produced IL-2, IFN-gamma, and TNF upon in vitro cultures. This was previously demonstrated to be a result of collaboration between tumor-primed CD4+ T cells and APCs binding CSA1 M tumor Ags in vivo. The IL-2- and IFN-gamma-producing capacities decreased with the progress of tumor-bearing stages. This was parallel to the levels of IL-2 and IFN-gamma mRNAs expressed by cultured spleen cells. In contrast, comparable levels of TNF mRNA were expressed by all groups of cultured cells. However, large amounts of TNF were secreted by the cells from early but not from late tumor-bearing mice. TNF was produced mainly by the non-T cell fraction upon stimulation with CD4+ T cell-derived IFN-gamma. Therefore, the reduced TNF production by whole spleen cells from late tumor-bearing mice was restored by addition of rIFN-gamma to their cultures. Reciprocally to the progressive decrease in the production of IFN-gamma/TNF, the capacities of tumor-bearing mice to produce TGF-beta and IL-6 increased along with tumor growth. TGF-beta suppressed production of IL-2, IFN-gamma, and TNF, but not of IL-6. Moreover, IFN-gamma/TNF production was negatively regulated by IL-6. Taken together with the fact that the growth of CSA1 M cells is completely inhibited by the combination of TNF and IFN-gamma, these results demonstrate that the tumor-bearing state induces an abnormal cytokine network under which the production of antitumor cytokines is negatively regulated.
接种CSA1 M细胞2至3周后，携带同基因肿瘤（CSA1 M）的BALB/c小鼠的脾细胞在体外培养时可产生白细胞介素-2（IL-2）、γ干扰素（IFN-γ）和肿瘤坏死因子（TNF）。此前已证明，这是肿瘤致敏的CD4 + T细胞与体内结合CSA1 M肿瘤抗原的抗原呈递细胞（APC）之间协作的结果。随着荷瘤阶段的进展，产生IL-2和IFN-γ的能力下降。这与培养的脾细胞表达的IL-2和IFN-γ mRNA水平平行。相比之下，所有培养细胞组表达的TNF mRNA水平相当。然而，早期荷瘤小鼠的细胞分泌大量TNF，而晚期荷瘤小鼠的细胞则不分泌。TNF主要由非T细胞部分在受到CD4 + T细胞衍生的IFN-γ刺激时产生。因此，通过向晚期荷瘤小鼠的全脾细胞培养物中添加重组IFN-γ，可恢复其降低的TNF产生。与IFN-γ/TNF产生的逐渐减少相反，荷瘤小鼠产生转化生长因子-β（TGF-β）和IL-6的能力随着肿瘤生长而增加。TGF-β抑制IL-2、IFN-γ和TNF的产生，但不抑制IL-6的产生。此外，IL-6对IFN-γ/TNF的产生具有负调节作用。结合TNF和IFN-γ联合可完全抑制CSA1 M细胞生长这一事实，这些结果表明荷瘤状态诱导了一种异常的细胞因子网络，在该网络下抗肿瘤细胞因子的产生受到负调节。
